Sulfamide antifolates inhibiting thymidylate synthase: synthesis, enzyme inhibition and cytotoxicity

• Published in: Acta biochimica polonica Vol. 49; no. 2; pp. 407 - 420
• Main Authors: Pawełczak, Krzysztof, Makowski, Maciej, Kempny, Michał, Dzik, Jolanta M, Gołos, Barbara, Rode, Wojciech, Rzeszotarska, Barbara
• Format: Journal Article
• Language: English
• Published: Poland 01-01-2002
• Subjects: Animals; Carcinoma, Ehrlich Tumor - enzymology; Carcinoma, Ehrlich Tumor - pathology; Cell Division - drug effects; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - toxicity; Folic Acid Antagonists - chemical synthesis; Folic Acid Antagonists - pharmacology; Folic Acid Antagonists - toxicity; Kinetics; Liver - enzymology; Mice; Molecular Structure; Rats; Sulfonamides - chemical synthesis; Sulfonamides - pharmacology; Sulfonamides - toxicity; Thymidylate Synthase - antagonists & inhibitors; Thymidylate Synthase - metabolism
• ISSN: 0001-527X; 1734-154X
• DOI: 10.18388/abp.2002_3799

Synthesis and biological evaluation are described of seven new analogues (3-9) of two potent thymidylate synthase inhibitors, 10-propargyl-5,8-dideazafolate (1) and its 2-methyl-2-deamino congener ICI 198583 (2). While the new compunds 3 and 4 were analogues of 1 and 2, respectively, containing a p-aminobenzenesulfonyl residue in place of the p-aminobenzoic acid residue, the remaining 5 new compounds were analogues of 4 with the L-glutamic acid residue replaced by glycine (5), L-valine (6), L-alanine (7), L-phenylglycine (8) or L-norvaline (9). The new analogues were tested as inhibitors of thymidylate synthases isolated from tumour (Ehrlich carcinoma), parasite (Hymenolepis diminuta) and normal tissue (regenerating rat liver) and found to be weaker inhibitors than the parent 10-propargyl-5,8-dideazafolic acid. Selected new analogues, tested as inhibitors of growth of mouse leukemia L 5178Y cells, were less potent than the parent 10-propargyl-5,8-dideazafolic acid. Substitution of the glutamyl residue in compound 4 with L-norvaline (9) resulted in only a 5-fold stronger thymidylate synthase inhibitor, but a 40-fold weaker cell growth inhibitor.